Affective disorders and depression in particular, impact a large segment of the population. Due to its polygenic nature, determining the mechanisms involved in the development of psychopoathology is a difficult task. Although studies suggest that early life experience has an important role in the susceptibility or resilience to depression, and that in humans, adults frequently encounter chronic social stress prior to the onset of depression, no studies look at the combination of these two stressors. The goal of this research is to systematically investigate mechanisms by which vulnerability to depression may occur. In order to test the hypothesis that early life adverse experience alters developing neurocircuitry and neuroendocrinology, increasing susceptibility to depressive-like affect, we propose to use a prenatal chronic variable stress (CVS) paradigm, in which dams are exposed to an unpredictable, non-habituating mild stress paradigm. Pups will be raised according to standard husbandry techniques. As adults, half of each group will be assigned to either control housing or housing in our seminatural model of social stress, the visible burrow system (VBS). As rats are social creatures and develop dominance hierarchies, we find that social subordination is an ideal chronic stressor, and subordinate (SUB) rats develop many symptoms that are characteristic of human depression, including anhedonia, decreased motivation, and dysregulation of serotonergic transmission and the HPA axis. The specific aims of this proposal are: 1) to test the hypothesis that male rats exposed to prenatal stress are more likely to become subordinate when socially housed, and that these rats will experience more profound changes in behavioral and neuroendocrine parameters associated with depression, and 2) to determine neurochemical changes that may underlie these changes, with particular attention to the serotonergic system and HPA axis. PUBLIC HEALTH RELEVANCE: The studies proposed are of public health interest, because they aim to determine the mechanisms by which early life stress confers susceptibility to affective disorders, which affect a significant proportion of the population. These studies use a rodent prenatal stress paradigm and the VBS, a chronic social stress model to test the hypothesis that prenatal stress will impart a vulnerability to stress and depressive-like behavior upon exposure to chronic social stress in adulthood. By understanding the mechanisms by which this susceptibility develops, it may be possible to identify new targets for the prevention or amelioration of symptoms associated with mood disorders.